Inhibition of nNOS activity in rat brain by synthetic kynurenines: structure-activity dependence.

The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process participating in neurodegeneration that characterizes some neurological disorders and acute cerebral insults. In looking for compounds with neuroprotective properties, a series of kynurenine derivatives were synthesized, and their effects on both the NMDA and nNOS activity in rat striatum were evaluated. Two compounds, 15a (2-acetamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) and 15c (2-butyramido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid), displayed more potent activities than the other synthetic compounds tested for the inhibition of NMDA excitability and nNOS activity. Two other compounds, 18a (2-acetamido-4-(3-methoxyphenyl)-4-oxobutyric acid) and 18c (2-butyramido-4-(3-methoxyphenyl)-4-oxobutyric acid), that have the same structure as 15a and 15c, except the amino group in R(1), showed different effects. Whereas compound 18a showed lower electrophysiological potency than compounds 15a and 15c in the inhibition of the NMDA-dependent excitability, compound 18c showed the opposite effect. Moreover, compounds 18a and 18c were unable to modify nNOS activity. The remaining kynurenines tested behave like compound 18a. These results suggest that a structure-related activity of these synthetic kynurenines and a N-H bond in a specific direction is necessary for some kynurenine analogues to inhibit nNOS activity.     

Microwave‐Assisted Synthesis and Tyrosinase Inhibitory Activity of Chalcone Derivatives

A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5‐hydroxy‐2‐(hydroxymethyl)‐4H‐pyran‐4‐one). Specifically, 1‐(‐1‐(4‐methoxyphen‐ yl)‐3‐phenylallylidene)thiosemicarbazide ( 18 ) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μm . The inhibition mechanism analysis of 1‐(‐1‐(2,4‐dihydroxyphenyl)‐3‐phenylallylidene) thiosemicarbazide ( 16 ) and 1‐(‐1‐(4‐methoxyphenyl)‐3‐phenylallylidene) thiosemicarbazide ( 18 ) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest.     

Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity

Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities comparable to pentazocine but showed no significant physical dependence liability. From these results, it is suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and its surrogates, and belong to a new series of compounds having a potent analgesic activity.     

Synthesis, pharmacological activity and biopharmaceutical characteristics of alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetates

The pro-drugs of alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid(I) with a potent anti-inflammatory activity were synthesized in order to reduce its gastrointestinal side effects. Various esters synthesized were evaluated for their anti-inflammatory activity and ulcerogenicity. Among the compounds maintaining a potent activity of I, N,N-dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate (II-18) showed excellent biopharmaceutical characteristics. The ulcerogenic effect of II-18 on the rat gastric mucosa was about 3 times less than that of I. It was suggested that II-18 may be an useful biolabile pro-drug for I among the compounds tested.     

1-苯甲酰基-4-(4-氯苄基)哌嗪衍生物的设计、合成以及抗炎活性研究

目的:以1-苯甲酰基-4-(4-氯苄基)哌嗪为先导化合物,经进一步的结构优化,期望获得一类抗炎活性更好的多靶点抑制剂。方法:以取代苯甲酸为起始原料,经取代、酰化反应合成18个目标化合物。测定所有化合物对脂多糖(lipopolysaccharide,LPS)诱导RAW264.7细胞分泌肿瘤坏死因子(tumor necrosis factor,TNF)-α和白细胞介素(interleukin,IL)-6的抑制作用,并对活性较好的化合物进行分子对接。结果:所有化合物均经¹H NMR,¹³C NMR,HRMS确定其结构,化合物3d,8k对TNF-α的分泌具有较好的抑制活性,化合物3b,3d对IL-6的分泌具有较好的抑制活性。结论:化合物3d对LPS诱导RAW264.7细胞分泌TNF-α和IL-6具有较好的抑制活性,有进一步研究的价值。     

Synthesis and antimicrobial activity of N-[(alpha-methyl)benzylidene]-(3-substituted-1,2,4-triazol-5-yl-thio) acetohydrazides

In this study 18 new hydrazones have been synthesized by reacting ortho- or para-substituted acetophenones with (3-substituted-1,2,4-triazol-5-yl-thio)acetohydrazide in ethanol. The prepared compounds were tested for antimicrobial activity. The prepared compounds exhibited only poor activity against Gram (+) and Gram (-) bacteria with the minimal inhibitory concentration (MIC) > or = 400 micrograms/ml. Moderate activity was observed against Candida species with MIC in the range 100-400 micrograms/ml.     

Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure-activity relationships

Glycyrrhizic acid (18β-GL or GL) is a herbal drug with a broad spectrum of antiviral activities and pharmacological effects and multiple sites of action. Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). Here we tested the effects of 15 GL derivatives against EBV infection by scoring the numbers of cell expressing viral antigens and quantifying EBV DNA copy numbers in superinfected Raji cells. The derivatives were made either by transformation of GL on carboxyl and hydroxyl groups or by conjugation of amino acid residues into the carbohydrate part. We identified seven compounds active against EBV and all showed dose-dependent inhibition as determined by both assays. Among these active compounds, the introduction of amino acid residues into the GL carbohydrate part enhanced the antiviral activity in three of the seven active compounds. However, when Glu(OH)-OMe was substituted by Glu(OMe)-OMe, its antiviral activity was completely abolished. Introduction of potassium or ammonium salt to GL reduced the antiviral activity with no significant effect on cytotoxicity. The -isomer (18-GL) of 18β-GL was as potent as the β-form, but its sodium salt lost antiviral activity. The metabolic product of GL, 18β-glycyrrhetinic acid (18β-GA or GA), was 7.5-fold more active against EBV than its parental compound GL but, concomitantly, exhibited increased cytotoxicity resulting in a decreased therapeutic index.     

Synthesis and pharmacological evaluation of fluorine-containing D₃ dopamine receptor ligands

A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D(2), D(3), and D(4) receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D(3) (K(i) = 0.17-5 nM) and moderate to high selectivity for D(3) vs D(2) receptors (ranging from ～25- to 163-fold). These compounds were also evaluated for intrinsic activity at D(2) and D(3) receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D(2) vs D(3) receptors. These compounds may be useful for behavioral pharmacology studies on the role of D(2)-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D(3) receptor (K(i) = 0.17 nM for D(3), 163-fold selectivity for D(3) vs D(2) receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D(3) receptor expression.     

Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents

A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.     

New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics

A series of novel substituted pyrimidinones and fused pyrimidinones (compounds 3 – 18 ) were synthesized starting with oxiranylmethanone 2 . The in vitro cytotoxicity against a human breast adenocarcinoma (MCF‐7) cell line was investigated and most of the tested compounds showed potent cytotoxic activity against the MCF‐7 cell line comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF‐7 cells with increasing doses (2, 5, 10, and 20 µg/mL) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF‐7 cells. In general, derivatives 11 and 16 revealed the highest anticancer activity among the tested compounds.     

Synthesis and antiviral activity of thiosemicarbazone derivatives of pyridazinecarbaldehydes and alkyl pyridazinyl ketones

Various novel thiosemicarbazones (TSCs) 15b-e, 16b-e, 17b-e, 18b-e, and 19b-e derived from 4-pyridazinecarbaldehyde, 3-pyridazinecarbaldehyde, 4-acetylpyridazine, 3-acetylpyridazine, and 3-propionylpyridazine were prepared and their cytotoxic and antiherpetic potentials were evaluated. It was found that the replacement of the 2-pyridylmoiety in aldehyde derived compounds 20a-c by a 4-pyridazinyl group (compounds 15b-d) abolishes biological activity. However, in TSCs derived from 3-pyridazinecarbaldehyde (16b-d) the cytotoxic potency was considerably reduced (factor approximately 300), while the antiviral activity was largely retained. A total loss of biological activity occurred when the pyridyl group in TSC 20d, derived from 2-acetylpyridine, was replaced by the 4-pyridazinyl system (17d). By employment of the 3-pyridazinyl unit for isosteric modification, however, the cell toxicity could be reduced significantly (factor 100) without impairing the antiherpetic potential also in the series of TSCs derived from N-heteroaromatic ketones. It was observed that there is no obvious influence of the size of the cycloamino substituent on the biological activities in compounds 20a-d, 15b-d, 16b-d, 17b-d, and 18b-d. While the pyridine derived TSCs in our experiments proved clearly cytotoxic at lower concentrations than those being antivirally active, the aza-analogous compounds derived from 3-acetylpyridazine (18b-e) inhibited plaque formation at concentrations equal to those causing cytotoxic effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diterpenes isolated from Croton zambesicus inhibit KCl-induced contraction

A mixture of two new diterpenes was isolated from a dichloromethane extract of Croton zambesicus: ent-18-hydroxytrachyloban-3beta-ol (1) and ent-18-hydroxyisopimara-7,15-diene-3beta-ol (2). The two compounds crystallised together and were separated after derivatisation of the pimarane derivative with osmium tetroxide. The structure of 1 was elucidated by 1D- and 2D-NMR analysis and by X-ray diffraction of a crystal containing both compounds while 2 was only identified by crystallographic data. As this plant is widely used in African folk medicine against hypertension, we have analysed the vasorelaxant activity of the isolated molecules. The mixture of the two compounds inhibited the KCl-induced contraction of male Wistar rat aorta (IC (50) = 1 microg/mL), while the purified trachylobane (compound 1) and the hydroxylated pimarane showed a lower activity than the mixture.     

Novel brominated quinoline and pyrimidoquinoline derivatives as potential cytotoxic agents with synergistic effects of γ-radiation

New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrimidoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2-enone 3. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 9, 11, 17 and 18 showed IC(50) values (36.4, 39.7, 39.02 and 36.4 μM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 32.02 μM). On the other hand, compound 6, 14 and 19 exhibited better activity than doxorubicin with IC(50) values of 8.5, 23.5 and 23.7 μM. Additionally, the most potent compounds 6, 14 and 19 were evaluated for their ability to enhance the cell killing effect of γ-radiation.     

Synthesis and pharmacological characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl derivatives as dopamine receptor ligands.

2-(4-Chloro-3-hydroxyphenyl)ethylamine (4) and some derivatives were synthesized as dopamine (DA) receptor ligands. Amine 4 retains the dopaminergic pharmacophore 2-(3-hydroxyphenyl)-ethylamine, and the chlorine atom replaces the "para" hydroxyl group of DA. The derivatives 18a-e were obtained by introducing on the nitrogen of amine 4 the n-propyl and 2-phenylethyl or 3-phenylpropyl groups which can be accommodated by the D-2 receptor lipophilic sites 3C and pi 3, respectively. The affinity and selectivity of these compounds for D-1 and D-2 subtypes was determined in radioligand competition assays for the DA receptors of rat striatum membranes using [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. The amine 4 shows about 7-fold lower affinity than DA for both sites and is not able to discriminate between the two subtypes of DA receptors. The introduction of two n-propyl groups (18a) on the nitrogen atom reduces by one-half and doubles the affinity for D-1 and D-2 binding sites, respectively. The substitution of an n-propyl group with different alkylphenyl groups, to give compounds 18b-e, increases the affinity for the D-2 subtype from 19-fold to 36-fold. These compounds have the same affinity at the D-2 site as the DA agonist N-n-propyl-N-(2-phenylethyl)-2-(3-hydroxyphenyl)-ethylamine (2a) and are about 20 times more selective than DA for this binding site. In the assay for D-2 receptor mediated inhibition of adenylate cyclase activity, all the tested compounds behaved as D-2 agonists; N-n-propyl-N-[2(4-hydroxyphenyl)ethyl]- (18d) and N-n-propyl-N-(2-phenyl-ethyl)-2-(4-chloro-3-hydroxyphenyl)ethylamine (18b) were more effective than DA or 2a. On the other hand, all compounds were less effective than DA in stimulation of adenylate cyclase activity in rat striatal homogenates, a kind of effect which is mediated by the D-1 subtype of DA receptors. These results suggest that the nitrogen substitution enhances the affinity and selectivity for the D-2 receptor. In the adenylate cyclase assay, the compounds behave as potent D-2 agonists.     

Synthesis of newer indolyl/phenothiazinyl substituted 2-oxo/thiobarbituric acid derivatives as potent anticonvulsant agents

2-Amino-5-(heteroarylmethylene)-1,3,4-oxadiazoles/thiadiazoles 7-10 were synthesized by cyclisation of 1-(heteroarylacetyl)semicarbazides/thiosemicarbazides 3-6. 5-(2'-Heteroarylmethylene-5'-aminomethylene-1',3,'4'- oxadiazol-2'-yl/thiadiazol-2'-yl)-2-oxo/thiobarbituric acids 11-18 were synthesized by condensation of compounds 7-10 at the 5th position of 2-oxo/thiobarbituric acids. The newly synthesized compounds showed anticonvulsant activity ranging from 50-90% (seizures protection). Compound 18 (5-(2'-phenothiazinylmethylene-5'-aminomethylene-1',3',4'-thiadiazol-2'- yl)-2-thiobarbituric acid) showed maximum activity being more potent than the reference drug phenytoin sodium (CAS 630-93-3).     

Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.     

Uncoupling of oxidative phosphorylation by glycyrrhetic acid, fusidic acid and some related triterpenoid acids

Some new derivatives of 18α- and 18β-glycyrrhetic acid and oleanolic acid were tested for their ability to inhibit phosphorylation coupled to succinate oxidation in rat liver mitochondria. Glycyrrhetic acid is a potent uncoupler of oxidative phosphorylation (approaching 2,4-dinitrophenol in potency); uncoupling activity is dependent upon each of the following functional groups: 3-hydroxy, 11-oxo and 30-carboxyl groups. Inversion of the configuration at C-18 (D/E ring junction) or replacement of the 11-oxo-12-ene system in ring C by the 9(11),12-diene system in glycyrrhetic acid abolished uncoupling activity. By contrast, the hemisuccinates (3-O-carboxypropionyl derivatives) of 18α-glycyrrhetic acid and of the 18β-9,12-diene acid were moderately potent uncoupling agents but less active than 18β-glycyrrhetic acid. The uncoupling activity of these hemisuccinates could not be attributed to the carboxypropionyl group alone. Structural analogues of various glycyrrhetic acid derivatives prepared from oleanolic acid (with the carboxyl group at C-28) were less active in uncoupling oxidative phosphorylation than the corresponding compounds in the glycyrrhetic acid series (with the carboxyl group at C-30). The uncoupling activity of some derivatives of two naturally occurring tetracyclic triterpenoid acids, polyporenic acid A and fusidic acid, was also investigated and found to largely depend upon their chemical structure. The possible application of these compounds as drugs in man is discussed.     

1,3‐Bis(aryloxy)propan‐2‐ols as potential antileishmanial agents

We describe herein the synthesis and antileishmanial activity of 1,3‐bis(aryloxy)propan‐2‐ols. Five compounds ( 2 , 3 , 13 , 17 , and 18 ) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC₅₀ < 15.0 μm ), and an influence of compound lipophilicity on activity was suggested. Most of the compounds were poorly selective, as they showed toxicity toward murine macrophages, except 17 and 18 , which presented good selective indexes (SI ≥ 10.0). The five more active compounds ( 2 , 3 , 13 , 17 , and 18 ) were selected for the treatment of infected macrophages, and all of them were able to reduce the number of internalized parasites by more than 80%, as well as the number of infected macrophages by more than 70% in at least one of the tested concentrations. Altogether, these results demonstrate the potential of these compounds as new hits of antileishmanial agents and open future possibilities for them to be tested in in vivo studies.     

Synthesis of variously 9,9-dialkylated octahydropyrimido [3,4-a]-s-triazines with potential antifungal activity

9,9-Dialkyloctahydropyrimido[3,4-a]-s-triazines were synthesized by iminodimethylation reaction between a 5,5-dialkyl-6-aminopyrimidine-2.4(3H,5H)-dione, a substituted aniline and two moles of formaldehyde. The synthesis of.5,5-dialkyl-6-aminopy-rimidinedione consisted of the condensation of urea with ethyl 2,2-dialkylcyanoacetates. 18 Octahydropyrimido[3,4-a]-s-triazines were synthesized and compounds resulting from a supplementary aminomethylation were also obtained. Most of these compounds were tested for antifungal activity in vitro. Only 9.9-dibutyl-6,8-dioxo-3(2-chlorophenyl)2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine showed some activity against Microsporum canis.